Identification of a novel endocytosis‑associated gene signature for prognostic prediction in lung adenocarcinoma

Zhang,Yixin; Liang,Siwen; Zhang,Yan; Liu,Minghui; Zhang,Kai

doi:10.3892/ol.2023.14098

Identification of a novel endocytosis‑associated gene signature for prognostic prediction in lung adenocarcinoma

Authors:
- Yixin Zhang
- Siwen Liang
- Yan Zhang
- Minghui Liu
- Kai Zhang
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Affiliations: Department of Blood Transfusion, Tianjin Hospital, Tianjin 300211, P.R. China, School of Optometry & Ophthalmology, Tianjin Medical University, Tianjin 300070, P.R. China, Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
Published online on: October 12, 2023 https://doi.org/10.3892/ol.2023.14098
Article Number: 511
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is one of the most common malignant solid tumors and the leading cause of cancer‑associated mortality worldwide. Endocytosis is an essential physiological activity for cells to maintain membrane homeostasis, and has been reported to serve an important role in tumorigenesis and progression. In the present study, the aim was to construct a prognostic prediction model of endocytosis‑associated genes for patients with lung adenocarcinoma (LUAD). The endocytosis‑associated gene signature was established using Lasso Cox regression analysis using the training set of the LUAD cohort from The Cancer Genome Atlas (TCGA) database, and verified using two datasets from the Gene Expression Omnibus (GEO) database. Kaplan‑Meier survival curves were used to evaluate the effectiveness of the prognostic evaluation of patients with LUAD. Differentially expressed genes were screened in the tumor tissue of patients compared with paired paracancerous tissues. A series of candidate genes associated to the prognosis of patients with LUAD was obtained using univariate Cox's regression analysis. Using the Lasso Cox regression analysis, an appropriate risk model with 18 endocytosis‑associated genes was established. A high‑risk score was positively correlated with a higher tumor stage and pathologic grade. Patients with LUAD and high‑risk scores had shorter survival times, increased intratumor heterogeneities and immune cell infiltration into tumor tissues, compared with those patients with LUAD and low‑risk scores. The endocytosis inhibitor chloroquine could repress proliferation and increase the apoptosis of lung cancer cells. In summary, a novel endocytosis‑associated gene signature was constructed using TCGA and GEO datasets. Patients with LUAD and high‑risk scores, as calculated by the signature, had a poor prognosis and short survival time.

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1	Nasim F, Sabath BF and Eapen GA: Lung cancer. Med Clin North Am. 103:463–473. 2019. View Article : Google Scholar : PubMed/NCBI
2	Li C, Lei S, Ding L, Xu Y, Wu X, Wang H, Zhang Z, Gao T, Zhang Y and Li L: Global burden and trends of lung cancer incidence and mortality. Chin Med J (Engl). 136:1583–1590. 2023. View Article : Google Scholar : PubMed/NCBI
3	Detterbeck FC, Boffa DJ, Kim AW and Tanoue LT: The eighth edition lung cancer stage classification. Chest. 151:193–203. 2017. View Article : Google Scholar : PubMed/NCBI
4	Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI
5	Duma N, Santana-Davila R and Molina JR: Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 94:1623–1640. 2019. View Article : Google Scholar : PubMed/NCBI
6	Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL and Paz-Ares L: Lung cancer: Current therapies and new targeted treatments. Lancet. 389:299–311. 2017. View Article : Google Scholar : PubMed/NCBI
7	Doherty GJ and McMahon HT: Mechanisms of endocytosis. Annu Rev Biochem. 78:857–902. 2009. View Article : Google Scholar : PubMed/NCBI
8	Lanzetti L and Di Fiore PP: Endocytosis and cancer: An ‘insider’ network with dangerous liaisons. Traffic. 9:2011–2021. 2008. View Article : Google Scholar : PubMed/NCBI
9	Théry C, Ostrowski M and Segura E: Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 9:581–593. 2009. View Article : Google Scholar : PubMed/NCBI
10	Chen PH, Bendris N, Hsiao YJ, Reis CR, Mettlen M, Chen HY, Yu SL and Schmid SL: Crosstalk between CLCb/Dyn1-mediated adaptive clathrin-mediated endocytosis and epidermal growth factor receptor signaling increases metastasis. Dev Cell. 40:278–288.e5. 2017. View Article : Google Scholar : PubMed/NCBI
11	Ketteler J and Klein D: Caveolin-1, cancer and therapy resistance. Int J Cancer. 143:2092–2104. 2018. View Article : Google Scholar : PubMed/NCBI
12	Roy S, Wyse B and Hancock JF: H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Mol Cell Biol. 22:5128–5140. 2002. View Article : Google Scholar : PubMed/NCBI
13	Kim B, Park YS, Sung JS, Lee JW, Lee SB and Kim YH: Clathrin-mediated EGFR endocytosis as a potential therapeutic strategy for overcoming primary resistance of EGFR TKI in wild-type EGFR non-small cell lung cancer. Cancer Med. 10:372–385. 2021. View Article : Google Scholar : PubMed/NCBI
14	Xiao GY, Mohanakrishnan A and Schmid SL: Role for ERK1/2-dependent activation of FCHSD2 in cancer cell-selective regulation of clathrin-mediated endocytosis. Proc Natl Acad Sci USA. 115:E9570–E9579. 2018. View Article : Google Scholar : PubMed/NCBI
15	Jo U, Park KH, Whang YM, Sung JS, Won NH, Park JK and Kim YH: EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR. Oncotarget. 5:1265–1278. 2014. View Article : Google Scholar : PubMed/NCBI
16	Nishimura Y, Bereczky B and Ono M: The EGFR inhibitor gefitinib suppresses ligand-stimulated endocytosis of EGFR via the early/late endocytic pathway in non-small cell lung cancer cell lines. Histochem Cell Biol. 127:541–553. 2007. View Article : Google Scholar : PubMed/NCBI
17	Nishimura Y, Yoshioka K, Bereczky B and Itoh K: Evidence for efficient phosphorylation of EGFR and rapid endocytosis of phosphorylated EGFR via the early/late endocytic pathway in a gefitinib-sensitive non-small cell lung cancer cell line. Mol Cancer. 7:422008. View Article : Google Scholar : PubMed/NCBI
18	Tanaka T, Ozawa T, Oga E, Muraguchi A and Sakurai H: Cisplatin-induced non-canonical endocytosis of EGFR via p38 phosphorylation of the C-terminal region containing Ser-1015 in non-small cell lung cancer cells. Oncol Lett. 15:9251–9256. 2018.PubMed/NCBI
19	Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:5502014. View Article : Google Scholar : PubMed/NCBI
20	Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA, et al: Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 4:26122013. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Park JV, Chandra R, Cai L, Ganguly D, Li H, Toombs JE, Girard L, Brekken RA and Minna JD: Tumor cells modulate macrophage phenotype in a novel in vitro co-culture model of the NSCLC tumor microenvironment. J Thorac Oncol. 17:1178–1191. 2022. View Article : Google Scholar : PubMed/NCBI
23	Park JE, Dutta B, Tse SW, Gupta N, Tan CF, Low JK, Yeoh KW, Kon OL, Tam JP and Sze SK: Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene. 38:5158–5173. 2019. View Article : Google Scholar : PubMed/NCBI
24	Tripathy S, Dassarma B, Roy S, Chabalala H and Matsabisa MG: A review on possible modes of action of chloroquine/hydroxychloroquine: Repurposing against SAR-CoV-2 (COVID-19) pandemic. Int J Antimicrob Agents. 56:1060282020. View Article : Google Scholar : PubMed/NCBI
25	Johannes L and Billet A: Glycosylation and raft endocytosis in cancer. Cancer Metastasis Rev. 39:375–396. 2020. View Article : Google Scholar : PubMed/NCBI
26	Cooper ST and McNeil PL: Membrane repair: Mechanisms and pathophysiology. Physiol Rev. 95:1205–1240. 2015. View Article : Google Scholar : PubMed/NCBI
27	Xiao Y, Rabien A, Buschow R, Amtislavskiy V, Busch J, Kilic E, Villegas SL, Timmermann B, Schütte M, Mielke T, et al: Endocytosis-mediated replenishment of amino acids favors cancer cell proliferation and survival in chromophobe renal cell carcinoma. Cancer Res. 80:5491–5501. 2020. View Article : Google Scholar : PubMed/NCBI
28	Azad T, Rezaei R, Surendran A, Singaravelu R, Boulton S, Dave J, Bell JC and Ilkow CS: Hippo signaling pathway as a central mediator of receptors tyrosine kinases (RTKs) in tumorigenesis. Cancers (Basel). 12:20422020. View Article : Google Scholar : PubMed/NCBI
29	Du Z and Lovly CM: Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 17:582018. View Article : Google Scholar : PubMed/NCBI
30	da Cunha Santos G, Shepherd FA and Tsao MS: EGFR mutations and lung cancer. Annu Rev Pathol. 6:49–69. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sim EH, Yang IA, Wood-Baker R, Bowman RV and Fong KM: Gefitinib for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 1:CD0068472018.PubMed/NCBI
32	Sartori G, Belluomini L, Lombardo F, Avancini A, Trestini I, Vita E, Tregnago D, Menis J, Bria E, Milella M and Pilotto S: Efficacy and safety of afatinib for non-small-cell lung cancer: State-of-the-art and future perspectives. Expert Rev Anticancer Ther. 20:531–542. 2020. View Article : Google Scholar : PubMed/NCBI
33	Remon J, Steuer CE, Ramalingam SS and Felip E: Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol. 29 (Suppl 1):i20–i27. 2018. View Article : Google Scholar : PubMed/NCBI
34	Wu SG and Shih JY: Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 17:382018. View Article : Google Scholar : PubMed/NCBI
35	Cruz Da Silva E, Choulier L, Thevenard-Devy J, Schneider C, Carl P, Ronde P, Dedieu S and Lehmann M: Role of endocytosis proteins in gefitinib-mediated EGFR internalisation in glioma cells. Cells. 10:32582021. View Article : Google Scholar : PubMed/NCBI
36	McCoach CE, Le AT, Gowan K, Jones K, Schubert L, Doak A, Estrada-Bernal A, Davies KD, Merrick DT, Bunn PA Jr, et al: Resistance mechanisms to targeted therapies in ROS1⁺ and ALK⁺ non-small cell lung cancer. Clin Cancer Res. 24:3334–3347. 2018. View Article : Google Scholar : PubMed/NCBI
37	Mamdani H, Matosevic S, Khalid AB, Durm G and Jalal SI: Immunotherapy in lung cancer: Current landscape and future directions. Front Immunol. 13:8236182022. View Article : Google Scholar : PubMed/NCBI
38	Chew HY, De Lima PO, Gonzalez Cruz JL, Banushi B, Echejoh G, Hu L, Joseph SR, Lum B, Rae J, O'Donnell JS, et al: Endocytosis inhibition in humans to improve responses to ADCC-mediating antibodies. Cell. 180:895–914.e27. 2020. View Article : Google Scholar : PubMed/NCBI
39	Sun J, Zhang Z, Bao S, Yan C, Hou P, Wu N, Su J, Xu L and Zhou M: Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer. J Immunother Cancer. 8:e0001102020. View Article : Google Scholar : PubMed/NCBI
40	Xie Q, Chu H, Yi J, Yu H, Gu T, Guan Y, Liu X, Liang J, Li Y and Wang J: Identification of a prognostic immune-related signature for small cell lung cancer. Cancer Med. 10:9115–9128. 2021. View Article : Google Scholar : PubMed/NCBI
41	Li B, Cui Y, Diehn M and Li R: Development and validation of an individualized immune prognostic signature in early-stage nonsquamous non-small cell lung cancer. JAMA Oncol. 3:1529–1537. 2017. View Article : Google Scholar : PubMed/NCBI
42	Sun S, Guo W, Wang Z, Wang X, Zhang G, Zhang H, Li R, Gao Y, Qiu B, Tan F, et al: Development and validation of an immune-related prognostic signature in lung adenocarcinoma. Cancer Med. 9:5960–5975. 2020. View Article : Google Scholar : PubMed/NCBI
43	Diao X, Guo C and Li S: Identification of a novel anoikis-related gene signature to predict prognosis and tumor microenvironment in lung adenocarcinoma. Thorac Cancer. 14:320–330. 2023. View Article : Google Scholar : PubMed/NCBI
44	Zhang L, Zhang Z and Yu Z: Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma. J Transl Med. 17:4232019. View Article : Google Scholar : PubMed/NCBI
45	Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, et al: Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 150:1121–1134. 2012. View Article : Google Scholar : PubMed/NCBI
46	Shi X, Kou M, Dong X, Zhai J, Liu X, Lu D, Ni Z, Jiang J and Cai K: Integrative pan cancer analysis reveals the importance of CFTR in lung adenocarcinoma prognosis. Genomics. 114:1102792022. View Article : Google Scholar : PubMed/NCBI
47	Ma S, Zhang L, Ren Y, Dai W, Chen T, Luo L, Zeng J, Mi K, Lang J and Cao B: Epiregulin confers EGFR-TKI resistance via EGFR/ErbB2 heterodimer in non-small cell lung cancer. Oncogene. 40:2596–2609. 2021. View Article : Google Scholar : PubMed/NCBI
48	Umeda Y, Hasegawa Y, Otsuka M, Ariki S, Takamiya R, Saito A, Uehara Y, Saijo H, Kuronuma K, Chiba H, et al: Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients. Oncogene. 36:6432–6445. 2017. View Article : Google Scholar : PubMed/NCBI
49	Peng DH, Ungewiss C, Tong P, Byers LA, Wang J, Canales JR, Villalobos PA, Uraoka N, Mino B, Behrens C, et al: ZEB1 induces LOXL2-mediated collagen stabilization and deposition in the extracellular matrix to drive lung cancer invasion and metastasis. Oncogene. 36:1925–1938. 2017. View Article : Google Scholar : PubMed/NCBI
50	Shi L, Xu Z, Yang Q, Huang Y, Gong Y, Wang F and Ke B: IL-7-Mediated IL-7R-JAK3/STAT5 signalling pathway contributes to chemotherapeutic sensitivity in non-small-cell lung cancer. Cell Prolif. 52:e126992019. View Article : Google Scholar : PubMed/NCBI
51	Ke B, Wei T, Huang Y, Gong Y, Wu G, Liu J, Chen X and Shi L: Interleukin-7 resensitizes non-small-cell lung cancer to cisplatin via inhibition of ABCG2. Mediators Inflamm. 2019:72414182019. View Article : Google Scholar : PubMed/NCBI
52	Kumar MS, Hancock DC, Molina-Arcas M, Steckel M, East P, Diefenbacher M, Armenteros-Monterroso E, Lassailly F, Matthews N, Nye E, et al: The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell. 149:642–655. 2012. View Article : Google Scholar : PubMed/NCBI
53	Koh HM and Song DH: Prognostic role of Rab27A and Rab27B expression in patients with non-small cell lung carcinoma. Thorac Cancer. 10:143–149. 2019. View Article : Google Scholar : PubMed/NCBI
54	Wu YJ, Nai AT, He GC, Xiao F, Li ZM, Tang SY, Liu YP and Ai XH: DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma. World J Surg Oncol. 19:2742021. View Article : Google Scholar : PubMed/NCBI
55	Ren Z, Hu M, Wang Z, Ge J, Zhou X, Zhang G and Zheng H: Ferroptosis-related genes in lung adenocarcinoma: Prognostic signature and immune, drug resistance, mutation analysis. Front Genet. 12:6729042021. View Article : Google Scholar : PubMed/NCBI
56	Xie M, Yu X, Chu X, Xie H, Zhou J, Zhao J and Su C: Low baseline plasma PCSK9 level is associated with good clinical outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer. Thorac Cancer. 13:353–360. 2022. View Article : Google Scholar : PubMed/NCBI